Project Summary Sepsis is a common and severe medical condition characterized by a systemic inflammatory response to infection. Currently, there is no effective treatment for sepsis, due to an incomplete understanding of the pathogenesis of this disorder. Identification of novel therapeutic targets that alleviate sepsis-induced systemic inflammation and prevent multi-organ injury is urgently required. One known controlling component of sys- temic inflammation is monocyte chemotactic protein-induced protein 1 (MCPIP1, also known as Zc3h12a or regnase-1), a ribonuclease that acts as a master controller of inflammation and immune homeostasis. As an RNase, MCPIP1 controls the production of numerous inflammatory cytokines and immune modifiers by direct degradation of their mRNAs and/or interfering with inflammatory signal pathways. MCPIP1 global knockout mice develop spontaneous ?inflammatory syndrome? characterized by heightened cytokine production, multi- organ inflammation and autoimmune response. These complex phenotypes suggest that MCPIP1 is func- tionally important in innate immune cells and in adaptive immune cells. However, the cell-specific functions of MCPIP1 in the pathological process of sepsis remain unclear. In this proposal, we have generated a novel myeloid-specific MCPIP1 knockout mouse line. Our recent studies demonstrated that myeloid MCPIP1 is critical for the protection of sepsis-induced systemic inflammation and organ injury. To understand the molec- ular mechanisms by which MCPIP1 RNase regulates systemic inflammation, we identified C/EBP? and C/EBP?, major transcriptional drivers of inflammation, as novel targets of MCPIP1 RNase. In addition, our preliminary studies show that MCPIP1, but not other MALT1 targets, is selectively cleaved by MALT1 in mac- rophages. Our central hypothesis is that MCPIP1 is crucial for the protection of host from sepsis-induced sys- temic inflammation and organ injury by limiting inflammatory cytokine production from macrophages, thus, enhancing MCPIP1 expression by inhibition of MALT1 may improve the outcome of sepsis. We will test this hypothesis with the following specific aims: 1) determine whether the expression of MCPIP1 in myeloid cells is essential in suppressing of sepsis-induced pathogenesis; 2) define the molecular mechanisms by which MCPIP1 suppresses sepsis-induced pathogenesis; 3) determine whether enhancing MCPIP1 expression by inhibition of MALT1 protease activity has a therapeutic potential for suppressing sepsis-induced pathogenesis and improving survival. Completion of these aims will not only significantly advance our understanding of the regulatory mechanisms of septic pathogenesis, but also identify a new therapeutic target to treat this devas- tating and life-threatening condition. Students have been and will continue to be a vital part of this research effort.